In 224 CE King of Persia Ardzashir V under Hormizdegan defeated his sovereign, King of Kings Artaban V, the last of the Arsacids, and assumed the throne of the suzerain of Iran as Ardashir I. The Parthians were replaced by the Sassanid dynasty. Philhellenism ended at the Ctesiphon court, Persian nationalism and Mazdaist fanaticism prevailed. Surrounded by the Zoroastrian clergy, the Sassanid kings made the expansion of their empire at the expense of Rome the idea of their reign, in order to match the achievements of the Achaemenids.
As early as 230 CE they attacked Rome-controlled western Mesopotamia. Emperor Severus Alexander approached Ctesiphon, where he failed. Ardashir, however, could not or could not take advantage of the victory. Success came a few years later when they took advantage of the chaos in the Roman Empire and took control of western Mesopotamia. In 243 CE The Great King Shapur I took Nisibis and Carrhae. Gordian III and the praetorian prefect, Tynesiteus, defeated Shapur’s army at Reshaina and drove them beyond the borders of the Empire. In 244 CE the new prefect, Philip the Arab, murdered Gordian and proclaimed himself emperor. He was defeated by the Persians at Ctesiphon and had to pay a contribution, relinquish any claims to Great Armenia, and not support the Armenian Arsacid efforts to overthrow the Sassanids. Western Mesopotamia, however, remained with the Romans.
In the year 252 CE, the troops of King Shapur I of the Kings conquered Antioch and the fortress of Dura Europos lying on the Euphrates, which the Romans took from the Parthians in 165 CE Shapur invaded Armenia and imprisoned his son, Hormizd. Four years later, near Edessa, the Roman emperor Valerian Valerian was captured along with many soldiers. Fortunately for Rome, the Sassanid march to the west was stopped by the troops of King Palmyra Odeantus, the imperial vassal, who became the only defenders of Rome’s eastern borders. Odenatus even conquered the Ktezyfont and was awarded the title corrector Orientis by Emperor Galien. In 283 CE Emperor Carus embarked on a great expedition to Iran, unheard of since Caracalia’s war with the Parthians. Roman troops captured Ctesiphon, but Emperor Carus, who led the campaign, died in mysterious circumstances in his own camp. In 284 CE western Mesopotamia remained with the Romans, while the Sassanids subjugated the Caucasian kingdom of Iberia.
In 296 CE the king of Persia Narses expelled King Tiridates V from Armenia and attacked the Roman Empire. He defeated the legions near Cahrrae. Emperor Galerius (Caesar Diocletian) came to the East and moved his operations to Armenia, where the Persian cavalry had been more difficult, and the legions that fought better there could have exploited it. In the Araxes Valley in the centre of the country, the Persian camp with the royal family fell into Roman hands. Galerius invaded Mesopotamia and took Ctesiphon. Despite the destruction of the Sassanid army, Emperor Diocletian did not annex the conquered lands, because he could hardly maintain order in the former empire. Only the border in Mesopotamia was changed in favour of the Romans.
In 359 CE the King of Kings Shapur II occupied many cities in northwest Mesopotamia. In 363 C.E. Emperor Julian the Apostate, dreaming of conquering Persia, went to war to the east. He made his way deep into Mesopotamia, but the expedition did not go well for the Roman troops. Although they reached Ctesiphon, they were not able to get it. Julian the Apostate withdrew to Armenia. From there, the Sassanids dragged him deep into Iran and harassed him with guerrilla warfare. The emperor was killed and the army faced the spectre of total destruction. Julian the Apostate’s successor, Jovian, saved the army and obtained a 30-year peace with the Sassanids in return for giving up most of western Mesopotamia.
After the division of the Roman empire in 395 CE, the wars continued. In 383 CE Emperor Theodosius I tried unsuccessfully to take part of Armenia from the Sassanids. In 428, Great King Bahram V annexed eastern Armenia and around 440 CE. Emperor Theodosius II did the same to the West. King Jazdagird II invaded the borders of the empire but quickly accepted the peace proposals. The battles of the Eastern Empire, and after the fall in 476 CE Rome of the Byzantine Empire, with the Sassanids, lasted until the 7th century CE.